Azacitidine favorably modulates PSA kinetics correlating with plasma DNA LINE-1 hypomethylation in men with chemonaïve castration-resistant prostate cancer

Sonpavde, Guru; Aparicio, Ana; Zhan, Feng; North, Brittany; Delaune, Robert; Garbo, Lawrence; Rousey, Steven R.; Weinstein, Ralph E.; Xiao, Lianchun; Boehm, Kristi A.; Asmar, Lina; Fleming, Mark T.; Galsky, Matthew D.; Berry, William R.; Hoff, Daniel D. Von

doi:10.1016/j.urolonc.2009.09.015

Cited by 58 publications

(36 citation statements)

References 27 publications

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“…26 LINE-1 methylation has been investigated as a screening tool for cancer detection in blood 27,28 and oral rinse samples 29 as well as a surrogate marker for predicting treatment response to chemotherapy. 30,31 Several studies have demonstrated an association between LINE-1 or ALU hypomethylation and poor clinical outcomes in cancer or clinicopathological parameters indicative of poor prognosis. 12,[32][33][34][35] However, little information is currently available about the prognostic value of repetitive DNA elements in GC.…”

mentioning

confidence: 99%

ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

Bae

Shin

Kwon

et al. 2012

Intl Journal of Cancer

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Focal CpG island hypermethylation and diffuse genomic hypomethylation signify the changes in the DNA methylation status in cancer cells. ALU and LINE-1 repetitive DNA elements comprise~28% of the human genome. PCR-based measurements of these repetitive DNA elements can be used as a surrogate marker of the genomewide methylation content. Our study aimed to identify the timing of ALU and LINE-1 hypomethylations during multistep gastric carcinogenesis and their prognostic implications in gastric cancer (GC). In our study, we analyzed the methylation statuses of ALU and LINE-1 in 249 cases of gastric biopsy samples and another independent set of 198 cases of advanced GC by pyrosequencing. Regardless of the Helicobacter pylori infection status, a significant decrease in the ALU methylation levels was noted during the transitions from chronic gastritis to intestinal metaplasia and from gastric adenoma to GC. LINE-1 methylation decreased during the transition from intestinal metaplasia to gastric adenoma and no further decrease occurred during the transition from gastric adenoma to GC. A low LINE-1 methylation status was strongly associated with poor prognosis in GC. A multivariate analysis revealed that LINE-1 methylation status was an independent prognostic factor. Our findings suggest that ALU and LINE-1 hypomethylations are early events during multistep gastric carcinogenesis. Furthermore, the LINE-1 methylation status can be used as a molecular biomarker to define a subset of GC patients with poor prognosis.Focal promoter CpG island hypermethylation and generalized genomic hypomethylation signify the changes in the DNA methylation status in human cancer cells. Promoter CpG island hypermethylation is an important mechanism that inactivates tumor suppressor and tumor-related genes; meanwhile, generalized genomic hypomethylation contributes to genomic or chromosomal instability.1-3 Genomic hypomethylation mainly affects repetitive transposable DNA elements, which comprise 45% of the human genome 4 ; these elements reside mainly in the intergenic and intronic regions of the genome and in noncoding and coding exons of the genome to a much lesser extent.5 Long interspersed nucleotide element-1 (LINE-1) and ALU are major constituents of interspersed DNA repeats, constituting $17% and 11% of the human genome, respectively. 4CpG sites located within LINE-1 and ALU are usually methylated in normal somatic tissues, a mechanism that is believed to have evolved as a major defense mechanism to repress these transposable genetic elements.6 Demethylation of transposable elements is hypothesized to facilitate genomic instability by leading to retrotransposition of transposable elements, hypomethylated genome-associated error-prone repair of replication-independent endogenous double-strand breaks, and dysregulation of DNA repair genes. [7][8][9][10][11] In addition to bringing about genomic structural variation, demethylation of transposable element promoters dysregulates gene expression by upregulating the transcription of genes l...

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mentioning

confidence: 99%

ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

Bae

Shin

Kwon

et al. 2012

Intl Journal of Cancer

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“…The RB1 gene is frequently deleted and methylated in CRPC, which points to a possible therapeutic option with hypomethylating agents, such as 5-azacytidine [51]. Azacytidine resulted in some PSA reduction in a phase II study of non-biomarker-selected CRPC [84]. Also, an animal study demonstrated higher sensitivity to cabazitaxel in CRPC tumour with loss of RB [85].…”

Section: Tmprss2-etsmentioning

confidence: 99%

Molecular landscape of prostate cancer: Implications for current clinical trials

Khemlina

Ikeda²,

Kurzrock³

2015

Cancer Treatment Reviews

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Castration-resistant prostate cancer (CRPC) is a lethal disease, and improvement with androgen-deprivation therapy has plateaued. Next-generation sequencing studies have led to significant advances in our understanding of genomic alterations in prostate cancer. The most common genomic aberrations in this malignancy are the transcription factor fusion of TMPRSS2-ETS, and mutations in TP53, AR, RB1 and PTEN/PIK3CA. Some of these alterations are actionable by drugs available in the clinic. In addition, it was recently shown that aberrations in DNA repair genes, such as BRCA2 and ATM, are present in both somatic and germline form in a significant minority of prostate cancer; these abnormalities can be targeted by drugs such as platinums and PARP inhibitors. In the era of tumour profiling, targeting molecular alterations may provide an opportunity for new therapeutic approaches. Although there are promising new agents to attack a variety of genomic signal abnormalities, biomarker-matched therapy (other than for androgens) have been utilised in only 2.0% of clinical trials (September 2011 through September 2014; https://clinicaltrials.gov) for prostate cancer. Enhanced efforts to define subsets of patients with prostate cancer based on their molecular anomalies, and match them with cognate therapies, warrant investigation.

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“…It has been shown by other research groups that the drug 5-azacytidine -currently FDA approved for the treatment of myelodysplastic malignancies -restores responsiveness of androgen-insensitive prostate tumors to androgen ablation therapy, even at relatively low doses (1)(2)(3)(4). This finding has triggered a strong and contemporary interest in the use of 5-azacytidine as a treatment modality for prostate cancers, possibly administered on a long-term basis in an early stage of the disease, in order to delay or avoid the onset of androgen-insensitivity.…”

Section: Short Backgroundmentioning

confidence: 99%

New Combination Therapies for Advanced Prostate Cancer Based on the Radiosensitizing Potential of 5-azacytidine

Weterings¹

2013

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE March 2013 REPORT TYPE Annual Report ABSTRACTThe research covered under this award is designed to further study our original finding that the epigenetic drug 5-azacytidine increases the responsiveness of prostate cancer cells and xenografts to radiation therapy by impairment of DNA double strand break repair. One of the most important goals of the project is to examine the efficacy of a combined regimen of 5-azacytidine, androgen ablation therapy, and radiation for treatment of advanced prostate cancers. We here present our second annual report, in which we demonstrate that combining 5-azacytidine with the two standard of care modalities for prostate cancer (androgen ablation and radiation) results in a temporary but complete control of tumor progression in a mouse model utilizing androgen-independent human-derived prostate cancer xenografts. Importantly, a single administration of the experimental regimen halted tumor progression for a period of a month, whereas tumors treated with radiation alone rapidly progressed during that period. Although tumors eventually resumed progression, the overall l time needed for triplication of the median volume was doubled as compared to the tumors treated with radiation alone. We expect that administration of repeat doses at the time of relapse, will further improve the overall outcome of the treatment, and we intend to further examine this hypothesis. We conclude that our proposed novel combination therapy of 5-azacytidine, androgen ablation, and radiation is indeed markedly more effective than the single modalities. These findings solidify the clinical potential of 5-azacytidine for treatment of advanced prostate cancers. In addition, our findings give further credibility to earlier observations that 5-azacytidine re-sensitizes advanced androgen independent tumors to andogen ablation therapy, thereby significantly expanding the applicability of this type of treatment. In the third year of the project, we aim to examine the effects of our treatment regimen on the metastatic potential of prostate tumors.

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Azacitidine favorably modulates PSA kinetics correlating with plasma DNA LINE-1 hypomethylation in men with chemonaïve castration-resistant prostate cancer

Cited by 58 publications

References 27 publications

ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

Molecular landscape of prostate cancer: Implications for current clinical trials

New Combination Therapies for Advanced Prostate Cancer Based on the Radiosensitizing Potential of 5-azacytidine

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